Download Gastroesophageal reflux disease: a review

ce
continuing education lesson
Gastroesophageal
reflux disease: a review
1.5
CEUs
SEPT 2004
■ Anisha Lakhani, B.ScPharm, PharmD
Objectives
Upon successful completion of this lesson, you should be able to:
1. describe the incidence, etiology and symptoms of gastroesophageal reflux disease (GERD)
2. identify the classification system for GERD and the various tests used to diagnose this
condition
3. describe common lifestyle modifications to help reduce GERD symptoms
4. discuss various over-the-counter and prescription drug treatment options for GERD
5. describe the role of the pharmacist in the management of GERD
eartburn, the hallmark symptom of gastroesophageal reflux disease (GERD), is
suffered by one-third of healthy individuals at
least once a month, while at least five per cent
of the population suffers from it daily.1,2 GERD
is a chronic, relapsing disease that causes significant morbidity in the lives of the individuals
who suffer from it, as well as significant costs
to the healthcare system.1 The terms “hiatus
hernia” and “reflux esophagitis” have been
replaced by the term GERD, which includes all
patients with reflux.
For many years, GERD has been recognized as a disease with a wide spectrum, ranging from mild reflux to severe esophagitis and
Barrett’s esophagus. Treatments range from
over-the-counter (OTC) products to prescription medications, and antireflux surgery. Many
patients choose to self-medicate with a variety
H
of OTC products; others need immediate medical attention and high-dose acid suppressive
therapy.3 This lesson will provide a step-wise
approach to the diagnosis and treatment of
GERD in adult patients.
Epidemiology
GERD affects both children and adults. Its true
prevalence rate and incidence are not clear
because not all patients seek medical attention.4 Secondly, many patients present with
atypical signs and symptoms, which makes
accurate diagnosis difficult. Thirdly, many epidemiological studies are hampered by inconsistent definitions used for the disease.5 Some
prevalence studies used questionnaires to
assess reflux symptoms, while others used
physiological criteria such as 24-hour pH
probe data and endoscopy results. Despite the
Instructions
1. After carefully reading this lesson, study each question and select the one answer you
believe to be correct. Circle the appropriate letter on the attached reply card.
2. Indicate if you are already registered as an annual CE Club Member or if you would like to
become a member.
3. Complete the card and mail, or fax to (416) 764-3937.
4. Your reply card will be marked and you will be advised of your results within six to eight
weeks in a letter from Pharmacy Practice.
5. To pass this lesson, a grade of 70 per cent (14 out of 20) is required. If you pass, your
CEU(s) will be recorded with the relevant provincial authority(ies). (Note: some provinces
require individual pharmacists to notify them.)
shortcomings, several epidemiological studies
provide the following facts about GERD in the
Western population:
• About seven per cent of Canadians seen by primary care physicians have functional dyspepsia,
which refers to upper abdominal discomfort.6
• About 25 per cent of pregnant women experience heartburn on a regular basis.7
• A survey of healthy hospital employees in the
U.S. found that seven per cent experienced
heartburn daily, and 14 per cent experienced
it weekly.8
• An endoscopy study in 355 otherwise
healthy individuals found that 13.8 per cent
had abnormal endoscopic findings (e.g.,
mucosal friability and erythema) and 8.5 per
cent had erosive esophagitis.9
Pathophysiology
While the actual cause of GERD is unknown, it is
well established that the pathophysiology involves
contact of noxious substances in the esophagus,
also referred to as the “offensive force.”10
Substances in the gastric refluxate that cause
damage to the mucosa include hydrochloric
acid, pepsin and, less likely, conjugated and
unconjugated bile salts and the pancreatic
enzymes tripsin and lipase.11 Interestingly,
patients with GERD do not necessarily produce
Supported by an unrestricted grant from
ce
Gastroesophageal reflux disease: a review
continuing education lesson
more acid or pepsin compared to healthy subjects.7,11 This suggests that GERD may be attributed to a breakdown of the defensive system
against damage by acid in the esophagus.
Defence system
The major components of the antireflux barrier are the lower esophageal sphincter (LES)
and the diaphragm. The role of the diaphragm
is to support the LES by physically encircling it
and providing mechanical support during
bending, stooping and running.11 The LES is
comprised of circular smooth muscle rings
located two to three centimeters from the distal end of the esophagus. It remains contracted at rest and relaxes upon swallowing.
Mechanisms that lead to an impaired
“defence system” and regurgitation in GERD
involve one or more of the following:11,12
• Incompetent LES
• Increased abdominal pressure due to gastric
distension, delayed gastric emptying or gastric
inflammation
• Increased frequency of transient LES relaxation
• Abnormal peristalsis
• Decreased tissue resistance against mucosal damage
Role of Helicobacter pylori
Helicobacter pylori, a gram-negative bacteria
found in the stomach, is a major pathogen in
duodenal and gastric ulcers. Its role in GERD is
controversial for several reasons. First, studies
have found that the incidence of H. pylori infection in subjects with GERD is no different from
that seen in healthy patients.13 Secondly, the
eradication of H. pylori in patients with dyspepsia has no impact on their symptoms of pain. In
fact, it has been suggested that H. pylori eradication may actually result in aggravation of
GERD symptoms in some patients.13,14 At this
time, there is no evidence to support benefit of
H. pylori eradication in patients with GERD.
TABLE 1
Symptoms of GERD
Typical symptoms
Heartburn
Regurgitation
Dyspepsia
“Sour stomach”
Atypical symptoms
Alarm symptoms
Cough
Hoarseness
Recurrent sore throat
Laryngitis
Substernal discomfort
Shortness of breath
Dysphagia
Gastrointestinal bleeding
Weight loss
Sensation of choking
Atypical non-cardiac chest pain
Routine testing and eradication of the organism,
if present, is not recommended due to a lack of
benefit in patients with GERD.15
Diagnosis
The term “gastroesophageal reflux disease”
encompasses both the manifestations of reflux
symptoms and endoscopic findings. A good
history and thorough physical exam are important steps in determining the initial diagnosis.
Symptoms of GERD are divided into typical or
atypical symptoms, as shown in Table 1. The
“alarm symptoms” point to severe disease or
carcinoma, and require thorough and immediate investigation.
Heartburn, the most common symptom of
GERD, occurs after eating, when lying down or
even when bending. About one-third of the
patients with GERD experience regurgitation.1,7
Often the effortless return of gastric contents into
the pharynx may result in hoarseness, laryngitis,
coughing or wheezing. It has been reported that
up to 50 per cent of patients with GERD-induced
asthma symptoms did not experience heartburn
but had other atypical symptoms.12 Respiratory
symptoms may be induced by aspiration of gastric contents into the lungs, which sets off a
vagal reflex that produces bronchoconstriction.12
Finally, reflux-induced chest pain is a common
cause of non-cardiac chest pain.
A thorough evaluation is required to rule
out cardiac or respiratory diseases before the
atypical symptoms are related to GERD.
Differential diagnosis for GERD includes gallstones, irritable bowel syndrome and peptic
ulcer disease.7,12
GERD is classified according to endoscopic and pathological findings as follows:
1. Non-erosive reflux disease (NERD): These
patients have mild to severe symptoms of GERD
but have negative endoscopic findings.10
2. Erosive esophagitis (EE): Erosion and exudative findings are the type of mucosal damage
found during endoscopy in these patients. Their
symptoms range from moderate to severe, and
progressive damage can occur to the mucosa
without treatment. A typical grading system used
to describe damage seen during endoscopy is
as follows: Grade 1 is mild, with edema and redness; Grades 2 and 3 include progression from
linear to confluent erosions within the
esophageal mucosa; and Grade 4 includes deep
ulcerations with strictures and the presence of
columnar epithelium. Grades 2 and 3 damage is
seen in patients with EE.
3. Barrett’s esophagus: This develops when
the squamous epithelium is replaced by intestinal columnar cells. This is Grade 4 damage
as described above.
4. Esophageal adenocarcinoma: The incidence of this is rare in the general population.
Patients with Barrett’s esophagus are at very
high risk of developing esophageal carcinoma.7
This diagnosis is made by taking a biopsy during an endoscopy and examining the specimen under the microscope.
CE Faculty
This month
CE Coordinator
Gastroesophageal reflux disease: a review
Brenda McBean Cochran, B.S.P., M.Sc.(Phm)
Pharmacist consultant, Bedford, N.S.
Author
Dr. Anisha Lakhani, B.ScPharm, PharmD, is
Drug Use Evaluation Coordinator at Fraser
Health; and Clinical Pharmacist in the Renal
Unit at Surrey Memorial Hospital, Surrey, B.C.
Reviewers
This lesson has been approved
for 1.5 CE units by the Canadian
Council on Continuing Education
in Pharmacy. CCCEP file # 140-0604
Approved for 1.5 CEUs by l’Ordre des
pharmaciens du Québec.
This lesson has been sponsored through
an unrestricted grant from Genpharm.
This CE lesson is published by Rogers
Media Healthcare/Santé, One Mount
Pleasant Rd., Toronto, ON M4Y 2Y5.
Tel.: (416) 764-3916 Fax: (416) 764-3931.
No part of this CE lesson may be reproduced,
in whole or in part, without the written
permission of the publisher.
All lessons are reviewed by three pharmacists for accuracy, currency and relevance
to current pharmacy practice.
2
Pharmacy Practice | September 2004
ce
Gastroesophageal reflux disease: a review
continuing education lesson
TABLE 2
Treatment approach
Stepwise approach to empiric therapy with acid suppressants7,16,17
GERD symptoms
Description of therapy*
Notes
Any symptoms of
GERD
• Lifestyle modifications
(see Table 3)
• Avoid drugs that worsen symptoms, if possible (see Table 4)
Continue throughout course
of therapy.
Empiric therapy for
mild and intermittent
heartburn
Antacids for two weeks
With or without
OTC H2RA products for two weeks
Use either or both for symptom relief. Seek medical attention if no relief in two weeks.
Empiric therapy for
“typical” symptoms
of GERD
Mild GERD:
Standard H2RA dose X 6-12 weeks
Moderate-severe GERD:
PPI X 4-8 weeks
Treat recurrences on an asneeded basis.
For patients who
• failed standard
H2RA therapy
• have “atypical” or
severe symptoms
• have erosive disease
High-dose H2RA X 8-12 weeks
Or
PPI X 8-12 weeks
High doses required for Barrett’s
esophagus
Maintenance therapy may be
warranted; endoscopy or other
investigation is warranted;
surgery may be warranted.
H2RA=Histamine2 receptor antagonists (cimetidine, famotidine, nizatidine and ranitidine)
PPI=Proton pump inhibitors (omeprazole, esomeprazole, lansoprazole, pantoprazole and
rabeprazole)
* Refer to Tables 6 and 7 for doses of H2RAs and PPIs.
Diagnostic tests for GERD
Patients who present with prolonged or atypical
symptoms of GERD are usually referred for further invasive tests to confirm or rule out the
diagnosis of GERD. Sometimes, invasive tests
are used to follow the progress in severe disease, after a period of treatment. The following
is a brief explanation of the various types of tests
used in GERD.
Barium swallow
This test involves X-ray imaging of the chest
after a barium “milk shake” is swallowed. The
barium coats the throat and esophagus and
reveals signs of thickening of esophageal folds,
as well as the presence and shape of hiatus
hernia, ulcerations and strictures. This test will
not detect mucosal inflammation or presence
of Barrett’s epithelial changes.
Esophageal manometry
A multi-lumen tube is passed into the stomach
and pressures are measured at various points
within the esophagus as the tube is pulled out.
This test is used to evaluate the peristalsis of
the esophagus (i.e., esophageal clearance),
and the function of the lower esophageal
sphincter. It can also be used to place an
ambulatory pH probe (for a 24-hour pH test).
relative information about reflux patterns, symptomatology and acidity. Studies have shown that
GERD symptoms are related to the degree and
duration of esophageal acid exposure (pH <4).11
Patients with more severe disease have a longer
esophageal acid (pH <4) exposure time than
those with milder disease.7
Endoscopy
Endoscopy involves passing a probe from the
mouth down the esophagus to visualize and
obtain biopsies. It provides information about
the extent of esophagitis, presence of Barrett’s
esophagus or neoplasm. Endoscopy is indicated in those with alarm or atypical symptoms,
or those who have persistent symptoms
despite adequate treatment.
“PPI trial”
Also known as the omeprazole test, this is oneor two-week empiric therapy with a proton
pump inhibitor. This trial is given to patients to
empirically diagnose GERD. If treatment provides symptom relief, then GERD is a likely
diagnosis. The PPI trial is often used prior to
endoscopy, or in patients with negative
endoscopy results.15
Treatment of GERD
Desired outcomes
24-hour ambulatory pH monitoring
An electrode pH probe is placed intranasally
down to an area just above the lower esophageal
sphincter. Patients keep a diary of pH and symptoms for 24 hours. This test provides useful corPharmacy Practice | September 2004
The immediate desired outcomes of treating
GERD are to eliminate symptoms and
decrease the frequency of recurrence. The
long-term goals are to heal the injured mucosa
and prevent further damage.
Pharmacological therapy is mainly directed
towards neutralizing or reducing acid production. Some patients will benefit from therapy
targeted toward increasing LES function and
improving gastric emptying. Studies show that
patients with mild and intermittent symptoms
benefit significantly with lifestyle modifications,
OTC acid suppressive therapy and antacids.
Patients with regular and more severe symptoms require standard dose or high-dose acid
suppressive therapy. A smaller percentage of
this population (i.e., with regular/severe symptoms) will require surgical interventions when
conservative treatment fails. Table 2 describes
a typical approach to empiric therapy.
Lifestyle modifications
All patients experiencing symptoms of GERD
should follow common lifestyle changes (see
Table 3). Well-designed trials measuring the
effects of lifestyle modifications in patients with
GERD are lacking. However, many experts
estimate that about 10-20 per cent of patients
will notice a significant benefit with lifestyle
changes alone.7,8,16 Patients should be advised
to maintain these changes throughout the
course of GERD therapy regardless of the
therapeutic modalities used.
Advise patients to start with changes in
eating habits, as these are easier to implement
and have immediate, even if temporary, relief.
The major (and probably more difficult)
lifestyle changes include smoking cessation,
avoidance of alcohol and weight loss. Smoking
lowers lower esophageal sphincter pressure
and aggravates reflux symptoms.7 Weight
reduction, if overweight, has been found to
help GERD symptoms simply because of
reduction in abdominal pressure and
improved dietary habits.12,16
Lastly, it is important to review patients’
profiles to see if they are taking any drugs that
promote reflux or that are known to irritate gastric mucosa (see Table 4). Drugs that cause an
irritant effect should be taken with a glass of
water if they cannot be avoided.
Antacids
The effectiveness of antacids in GERD depends
on their neutralizing capacity on the acid secretions. Antacids raise the pH of the gastric contents above 4 and thereby inhibit the conversion
of pepsinogen to pepsin. Neutralization of gastric acid also increases LES pressure, and helps
to reduce the frequency of reflux. Evidence
from randomized trials shows antacids to be
3
ce
Gastroesophageal reflux disease: a review
continuing education lesson
superior over placebo; however, endoscopic
data and data on long-term efficacy are lacking.7,18 Antacids can be used as needed for
symptom relief and are fast-acting. The disadvantage is that they are short-acting (two to
three hours) and require frequent large doses.
Antacids come in single compounds such
as aluminum hydroxide, calcium carbonate or
magnesium hydroxide. They also come in
combinations that include alginic acid. Alginic
acid forms a highly viscous solution and serves
as a barrier for reflux, as it floats on the surface
of the gastric contents. Antacids with alginic
acid as combination products are more effective than the single component alone.7 Table 5
shows examples of common regimens used.
Antacids have few side effects but may
cause acid-base disturbances or alterations in
mineral metabolism. The pharmacist should
provide the following advice when counselling
patients on the use of antacids:7,15
• Antacids and alginic acid products are appropriate for temporary relief of mild symptoms.
• Patients with diabetes should be advised to
use sugarless products.
• Aluminum-containing antacids bind to phosphate in the gut and may lead to bone demineralization with long-term use.
• Aluminum-containing antacids may cause
constipation. Magnesium-containing products
may cause diarrhea. Use combination products to avoid these side effects.
• Both aluminum and magnesium accumulate in
patients with renal failure. Avoid in these patients.
• Sodium bicarbonate-containing antacids
should be avoided in patients with renal failure, congestive heart failure or hypertension,
and in patients on a sodium-restricted diet.
• Antacids increase gastric as well as urinary
pH and react with many compounds to form
insoluble complexes. Hence, space antacids
two hours before or six hours after taking any
of the following medications:
- Tetracycline
- Ferrous sulfate (space as much as possible)
- Isoniazid
- Sulfonylureas
- Fluoroquinolones
• Large doses of antacids interfere with the
absorption of phenytoin, digoxin and histamine2 receptor antagonists (H2RA), among
others. Monitor the levels of phenytoin and
digoxin if antacids are used concomitantly.
• Space antacids two hours before or after the
use of cimetidine, nizatidine or ranitidine, as
antacids significantly reduce their absorption
by up to 35 per cent.20 Famotidine may be
4
TABLE 3
Lifestyle modifications for GERD7,8,16,18
•
•
•
•
Avoid tight-fitting clothes
Elevate head of the bed by four to eight inches
Weight loss (for obese patients)
Dietary changes
- Eat smaller meals more frequently
- Decrease dietary fat
- Do not eat within three hours of bedtime
- Avoid foods with irritant effect (citrus fruits and juice, tomato-based juice and
sauces, coffee, pepper, spicy foods)
- Avoid foods that reduce LES pressure (chocolate, spearmint and peppermint)
• Stop smoking
• Avoid alcohol
LES=lower esophageal sphincter
TABLE 4
Drugs that promote reflux*,7,16,18
• If possible,** avoid drugs that promote reflux by either reducing the LES tone or gastric
emptying:
- Anticholinergics (e.g., phenothiazines, tricyclic antidepressants)
- Theophylline preparations
- Calcium channel blockers
- Beta-agonists
• If possible,** avoid drugs that have an irritant effect on esophageal mucosa:
- Tetracycline
- Quinidine
- Potassium supplements
- Iron salts
- ASA
- NSAIDs
- Bisphosphonates
* This is not a complete list. Other drugs may require precautions in patients with GERD.
** If these drugs cannot be avoided, they should be taken with a full glass of water.
ASA=acetylsalicylic acid
NSAIDs=nonsteroidal anti-inflammatory drugs
TABLE 5
Common antacid regimens7,12,19
Antacid
Typical dose (administered
as needed, PC and HS)
Magnesium hydroxide 70 mg/mL
30 mL
Aluminum hydroxide 64 mg/mL
30 mL
Magnesium hydroxide 40 mg/mL +
aluminum hydroxide 40 mg/mL
30 mL
Aluminum hydroxide 20 mg/mL +
sodium alginate 50 mg/mL
30 mL
Magnesium carbonate 40 mg + alginic acid 200 mg
Magaldrate 96 mg/mL
Calcium carbonate (e.g., chewable 500 mg;
chewable ultra 1000 mg)
2 tablets
30 mL
1 or 2 regular tablets
or 1 ultra tablet
PC=after meals; HS=at bedtime
taken with antacids as its absorption has been
found to be less affected.21
Histamine2 receptor antagonists
H2RAs competitively inhibit histamine at H2
receptor sites in gastric parietal cells, thereby
reducing gastric acid secretion. The first
H2RA, cimetidine, has been available for the
treatment of peptic ulcer disease in Canada
since 1977. These drugs have been used as a
group for the treatment of GERD since the
1980s. Randomized, placebo-controlled trials
have shown that about 70 per cent of patients
with heartburn experience relief after a few
weeks of therapy with an H2RA.1,22 Other studies have shown that H2RAs are effective for
mild but not moderate or severe GERD, or
endoscopically defined erosive esophagitis.23,24
Pharmacy Practice | September 2004
ce
Gastroesophageal reflux disease: a review
continuing education lesson
TABLE 6
H2RAs: Common doses, side effects and interactions*
Side effectsc
Drug interactionsc,d
Cimetidinea,b
Symptomatic relief:
200 mg OD-BID
Standard dose:
400 mg BID
High dose:
400 mg QID or
800 mg BID
• Mild, transient diarrhea, skin rash and hives
• CNS effects (1-10%) (headache, fatigue,
confusion); elderly have higher risk of CNS &
other side effects
• Prolonged use associated with gynecomastia:
weak androgenic potential
• Transient increase in LFTs, SCr
• Consult monograph for detailed explanation
• Inhibition of CYP450: accumulation of warfarin,
phenytoin, theophylline. Monitor for increased serum
levels and toxicity of these drugs.
• May potentiate therapeutic effect of benzodiazepines,
beta-blockers, calcium channel blockers, carbamazepine,
cisapride,e clozapine, sulfonylureas, paroxetine,
propafenone, quinidine, tricyclic antidepressants.
• Decreased absorption of azoles (e.g., ketoconazole,
itraconazole and fluconazole). Increase the dose of the
azole or consider an alternative.
Famotidinea,b
Symptomatic relief:
10 mg OD-BID
Standard dose:
20 mg BID
High dose:
40 mg BID
• Uncommon: diarrhea, constipation
• CNS side effects (1-5%)
• Little or no effect on CYP 450.
• Decreased absorption of azoles (requires acidic
environment). Increase the dose of the azole or consider
an alternative.
Nizatidineb
Symptomatic relief:
75-150 mg OD
Standard dose:
150 mg BID
High dose:
150 mg QID
• CNS side effects: dizziness (10%), headache
(up to 16%)
• Rash, pruritis
• Rare: elevation of LFTs
• Weak inhibitor of CYP 3A4; no significant interactions.
• Decreased absorption of azoles. Increase the dose of
the azole or consider an alternative.
Ranitidinea,b
Symptomatic relief:
75 mg OD-BID
Standard dose:
150 mg BID
High dose:
150 mg QID
• Mild diarrhea, skin rash, hives
• Rare CNS side effects
• Minor effect on CYP 2C19, 2D6.
• No significant drug interactions.
• Decreased absorption of azoles. Increase the dose of
the azole or consider an alternative.
Drug & dosage range7,15,18
* The above list includes common side effects and drug interactions and is not all-inclusive.
a Dosage adjustment required in renal failure. Consult individual monographs for dosage adjustments.
b Available as OTC product.
c Nonprescription drug reference for health professionals. Ottawa: Canadian Pharmacists Association; 2001.
d Adapted from: Hansten PD, Horn JR. Drug interactions analysis and management. Vancouver, WA: Applied Therapeutics; 1997.
e Cisapride has been removed from the market; available on Special Access Programme only.
CNS=central nervous system; LFTs= liver function tests; SCr= serum creatinine
As a class, the H2RAs are recommended
for initial therapy of mild GERD. Patients with
meal-related heartburn may benefit by using
an OTC H2RA product. Compared to antacids,
the H2RAs provide a more manageable, less
cumbersome dosing schedule. Patients seeking to use OTC H2RAs should be appropriately counselled about dosing, drug interactions
and side effects (see Table 6).
All four OTC H2RAs are available in approximately one-half of their prescription doses:
nizatidine 75 mg, cimetidine 100 mg and 200
mg, famotidine 10 mg and ranitidine 75 mg.
The latter two products are commonly available
on the pharmacy shelves. Patients with mealrelated symptoms should be advised to take
either of these drugs prior to a meal once, or at
the most twice, daily. Pharmacists should pay
attention to dosing adjustments for patients
with renal impairment. Patients who have only
nocturnal symptoms should be advised to take
Pharmacy Practice | September 2004
the H2RA prior to bedtime. An adequate trial
period involves daily use of an OTC product for
two weeks along with lifestyle changes.
Patients with insufficient relief of symptoms
should be referred to the physician for further
investigation (after two weeks, or earlier
depending on their symptoms).
Studies show that the healing rates with
H2RAs depend on the severity of the disease,
the dose of the H2RA (standard versus high) and
duration of therapy. In a study involving patients
with endoscopically defined mild (Grade 1)
esophagitis, the healing rate with high-dose
cimetidine (400 mg QID) for 12 weeks was 80
per cent, compared to only 46 per cent in
patients with severe (Grade 3) esophagitis.25
Significantly higher doses of H2RA were
required (famotidine 40 mg BID, nizatidine 150
mg TID) in clinical trials to show improved endoscopic healing rates (76-81%) when used for
prolonged duration (e.g., 12 weeks).26,27 There is
limited information about the long-term safety of
such high doses of H2RAs. Therefore, it is prudent to recommend standard doses to begin
with (see Table 6). Short courses of higher doses
may be attempted in carefully assessed patients
with close medical supervision.
Proton pump inhibitors
Proton pump inhibitors (PPIs) work on the surface of gastric parietal cells to inhibit H+/K+
adenosine triphosphate enzymes and prevent
the transport of the H+ ion in exchange for K+.
This occurs at the final step of acid production
and results in profound acid suppression.
Comparative studies show PPIs have at least 30
per cent higher response rates than H2RAs in
severe erosive and severe non-erosive GERD.28-30
There are five PPIs available on the market
(see Table 7). All have short half-lives and a long
duration of action, due to sustained acid suppression caused in the parietal cells. They are
5
ce
Gastroesophageal reflux disease: a review
continuing education lesson
generally well tolerated; side effects including
headache, somnolence, dizziness, diarrhea, constipation or nausea occur in less than five per
cent of the population. All PPIs are metabolized
by CYP 3A4 and CYP 2C19 in different degrees.
Pantoprazole, lansoprazole and rabeprazole have
not been involved in clinically significant CYP
enzyme system interactions, unlike omeprazole.1,7,15 There is insufficient experience regarding interactions with esomeprazole.
There is a growing body of evidence supporting the use of PPIs in severe GERD. A metaanalysis compared endoscopic outcomes and
symptom relief with the use of various H2RAs
and PPIs in patients with Grades 2 to 4 esophagitis. PPIs showed consistently faster healing rates
within two weeks (PPI 63.4% vs H2RA 30%).31
The overall healing rate for PPIs was 83.6 per
cent ± 11.4 per cent irrespective of dose, drug or
duration, and 51.9 per cent ± 17.1 per cent for
H2RAs at standard or higher doses. Similar findings were reported in a systematic review of 30
randomized controlled trials with endoscopic
healing as the outcome measure. Healing was
faster and more extensive with PPIs compared to
H2RAs at four weeks and eight weeks (relative
risk [RR] 2.0, 95% confidence interval 1.7-2.5 at
four weeks, and RR 1.7, 95% confidence interval 1.5-2.0 at eight weeks).32 These reviews substantiate the superiority of PPIs over H2RAs in
patients with severe, erosive GERD.
Today, PPIs are commonly prescribed for the
treatment of GERD. There has been some
debate about whether one PPI is superior over
another. A systematic review of 32 studies
showed that there were some differences. In
head-to-head trials, two PPIs (esomeprazole and
lansoprazole) showed superiority over omeprazole for speed of symptom relief.34 However,
after one to two weeks, all five agents had similar efficacy for maintaining symptom control. In
terms of healing rates, one study showed that
after eight weeks of treatment, esomeprazole 40
mg had superior healing rates compared to
esomeprazole 20 mg and omeprazole 20 mg
(94%, 90% and 87%, respectively, p <0.05).35
Many clinicians have questioned the clinical significance of these findings.34 Others have simply
pointed out that the 40 mg dose of esomeprazole (the S isomer of omeprazole) is effectively a
higher dose and unfair comparator to 20 mg
esomeprazole and 20 mg omeprazole.36
According to most guidelines, the choice of
PPI depends on cost and convenience, as
they are all found to be highly efficacious in
GERD. Higher doses of PPI may be required
(e.g., omeprazole 40-60 mg or lansoprazole
6
TABLE 7
PPI
Proton pump inhibitors: doses and interactions*
Interactions c,15
Dose7,15,18
Esomeprazolea Symptomatic: 20-40 mg OD • Reduces absorption of drugs that depend
Maintenance: 20 mg OD
on gastric pH for bioavailability (e.g., ketoconazole, iron salts).
Lansoprazolea
Symptomatic: 15-30 mg OD
Note: Short-term (4-8 week)
use of 30 mg BID has been
studied
Maintenance: 15 mg OD
• Reduces bioavailability of azoles (e.g.,
ketoconazole) and indinavir.
• May increase bioavailability of digoxin;
monitor levels.
Omeprazolea
Symptomatic: 20 mg OD
Note: Short-term (4-8 week)
use of 20 mg BID or TID
has been studied29
Maintenance: 20 mg OD
• Inhibits metabolism of carbamazepine,
cyclosporine, phenytoin, warfarin,
benzodiazepines.
• Reduces bioavailability of azoles (e.g.,
ketoconazole) and indinavir.
• May increase bioavailability of digoxin;
monitor levels.
Pantoprazoleb
Symptomatic: 40 mg ODd
Maintenance: 40 mg OD
• Reduces absorption of drugs that
depend on gastric pH for bioavailability
(e.g., ketoconazole, iron salts).
Rabeprazolea
Symptomatic: 10-20 mg OD • May increase bioavailability of digoxin.
to BID
Monitor levels.
Maintenance: 20 mg OD
* The above list includes common drug interactions and is not all-inclusive.
a Dosage adjustment necessary in severe hepatic failure.
b Patients who have difficulty swallowing may open capsules and sprinkle intact pellets or
granules of certain products (lansoprazole, omeprazole) in applesauce to then be swallowed.
c Information from product monographs in Compendium of Pharmaceuticals and
Specialties, 2004.
d No difference in four- and eight-week healing rate was found between 40 mg and 80 mg
doses of pantoprazole in GERD.33
TABLE 8
Prokinetic agents
Drug & dose
Therapeutic effect
Side effects7,18
Bethanechol 25 mg QID Cholinergic agonist
• Diarrhea, cramping, fatigue,
blurred vision.
Metoclopramide 10 mg
BID-TID
Smooth muscle stimulant, • Galactorrhea, menstrual dysinhibits dopamine receptors function, lethargy, extrapyramidal
side effects, tardive dyskinesia.
Cisapride 10 mg QID
(Withdrawn from the
market)
Stimulates acetylcholine
release, increasing LES
pressure
• Fatal cardiac arrhythmias when
used in combination with select
drugs.
• Available on Special Access
Programme only.
LES=lower esophageal sphincter
30-60 mg daily) in the initial treatment of
esophageal ulcers in patients with complicated
GERD. Most other patients with moderate to
severe uncomplicated GERD will achieve good
results with standard doses of any PPI.1,15, 34
There have been some concerns about
long-term use of PPIs. PPIs cause an increase
in gastrin production in the antral-G cells,
which may cause hypertrophy of the gastric
mucosa. However, there have been no reports
of PPI-associated gastric carcinoma after a
decade of PPI use in the U.S., Europe and
Australia.1 The second concern is possible
overgrowth of bacteria due to profound acid
suppression, which can predispose a patient
to severe infections. This concern has not
been substantiated. Nevertheless, a risk-benefit assessment has to be done with the longterm use of PPIs. The benefit with continuous
use of PPIs in patients with chronic or complicated GERD may override the risks.
Prokinetic agents
Table 8 summarizes information about prokinetic agents. The rationale for using prokinetic
agents in GERD comes from physiological eviPharmacy Practice | September 2004
ce
Gastroesophageal reflux disease: a review
continuing education lesson
dence suggesting that GERD may result from
dysfunction of the LES.14 However, a review from
the Cochrane database showed that efficacy of
prokinetics was similar to that of H2RAs in controlling symptoms and promoting endoscopic
healing of GERD.22 In general, prokinetic agents
have more side effects and limited efficacy compared to conventional acid suppressive therapy.
For example, bethanechol’s cholinergic action
potentiates esophageal peristalsis and LES pressure, but also results in an increase in gastric
acid secretion.1,7 This limits its use in GERD.
Combination treatment may benefit some
patients. One study showed that metoclopramide combined with an H2RA was more
effective than the H2RA alone at healing
esophagitis.37 However, metoclopramide has
many central nervous system (CNS) side
effects, the most problematic of which is tardive dykinesia.18 Cisapride has been studied
extensively for the treatment of GERD and was
found to have similar efficacy to H2RAs.
However, a pH monitoring study failed to show
a decrease in reflux compared to controls.38,39
Cisapride was withdrawn from the market in
the autumn of 2000 due to reports of fatal cardiac dysrhythmias associated with the combination of cisapride and other agents metabolized by the cytochrome P450 system.
Other agents being studied for a possible
role in GERD include tegaserod, domperidone
and erythromycin. Currently, acid suppressive
therapy remains the mainstay of therapy for
GERD.1,12,18
The pharmacist’s role
GERD is a chronic, relapsing disease in many
patients. A significant number of patients with
heartburn have erosive disease, which can
cause significant morbidity if not diagnosed and
treated appropriately. Pharmacists play an
important role in counselling patients about
GERD and identifying patients who have unusual symptoms that require medical assessment.
Pharmacists need to emphasize that
lifestyle changes are vital in the management
of GERD. Based on the type and severity of the
symptoms, the pharmacist can guide patients
on the appropriate use of OTC products.
Careful attention needs to be paid when counselling patients with chronic diseases such as
congestive heart failure, hypertension, renal
insufficiency and diabetes. Such patients are
on multiple drug therapies that may have
potential drug interactions with both OTC and
prescription medications for GERD. Finally,
patients with severe or unrelenting symptoms
should be referred immediately to their physician for further investigation and appropriate
treatment. Pharmacists can offer a valuable
service as they are readily available to counsel
patients on the proper use of GERD medications as well as their response to those medications, and to reinforce the need for adherence to the regimen. Pharmacists can also
advise patients when to seek medical attention
for their symptoms and/or the possibility of the
need for prescription therapy.
11. Orlando RC. Pathogenesis of gastroesophageal reflux
disease. Gastroenterol Clin N Am 2002;31:535-44.
12. Patti M, Deiener U, Fisichella PMA, et al.
Gastroesophageal reflux disease. Jan 2003. www.emedicine.com/med/topic857.htm (accessed April 5, 2004).
13. Laine L, Dhir V. Helicobacter pylori eradication does
not worsen the quality of life related to reflux symptoms: a
prospective trial. Aliment Pharmacol Ther 2002;16:1143-8.
14. Champion MC. Prokinetic therapy in gastroesophageal
reflux disease. Can J Gastroenterol 1997;11(Suppl B):55B-65B.
15. Goodman F, Roberts K, Allerman A. Veterans Health
Administration/Department of Defense clinical practice guidelines
for management of adults with gastroesophageal reflux disease in
primary care practice. Veterans Health Administration,
Department of Veterans Affairs. March 12, 2003: 1-58.
16. Willis J. Ch. 16. Gastrointestinal diseases. In: Carey
CF, Lee HH, Woeltje KF, editors. The Washington manual of
medical therapeutics. 29th ed. Philadelphia: Lippincott Raven
Publishers; 1998:309-11.
17. Galmiche JP, Shin G, Simon B, et al. On-demand
treatment of gastroesophageal reflux symptoms: a comparison
of ranitidine 75 mg with cimetidine 200 mg or placebo.
Aliment Phamacol Thera 1988;12(9):909-17.
18. Tutuian R, Castell DO. Management of gastroesophageal reflux disease. Am J Med Sci 2003;326(5):309-18.
19. Heidelbaugh JJ, Nostrant TT, Kim C, et al.
Management of gastroesophageal reflux disease. Am Fam
Physician 2003;1311-8, 1321-2.
20. Tatro DS, editor. Drug interaction facts. St. Louis, MO:
Wolters Kluwer Health Inc.; 2003.
21. Pepcid AC. CPS monograph. Johnson & Johnson,
Merck. 2004:1510.
22. van Pinxteren B, Numans ME, Bonis PA, et al. Shortterm treatment with proton pump inhibitors, H2 receptor
antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease.
Cochrane Database Syst Rev 2001:(4):CD002095.
23. Ciociola AA, Pappa KA, Sirgo MA. Nonprescription
doses of ranitidine are effective in the relief of episodic heartburn. Am J Thera 2001;8(6):399-408.
24. Kovacs TOG, Wilcox CM, Devault K, et al. Comparison of
the efficacy of pantoprazole versus nizatidine in the treatment of
erosive oesophagitis: a randomized, active-controlled, doubleblind study. Aliment Pharmacol Ther 2002;16(12): 2043-52.
25. Tygat GNJ, Nicolai JJ, Reman FC. Efficacy of different
doses of cimetidine in the treatment of reflux esophagitis.
Surgical interventions
Antireflux surgery may be recommended in
patients with physical defects with any major
component of the antireflux barrier: the lower
esophageal sphincter and the position of the
esophagus in relation to the diaphragm. Such
patients have tried and failed therapy with acid
suppression as well as prokinetic agents.
Antireflux surgery includes reduction of hiatal
hernia, repair of diaphragmatic hiatus, strengthening of gastroesophageal junction at the
diaphragm or placement of gastric wrap at the
gastroesophageal junction.19 Candidates for
antireflux surgery have to be carefully selected
after undergoing many diagnostic tests. A new
endoscopic treatment involving the use of
radiofrequency ablation to generate a scar tissue
at the LES is showing promising results.18 This
procedure is aimed at reducing transient LES
relaxation to reduce reflux. Unfortunately, antireflux surgery does not eliminate use of acid suppressive therapy in all patients.
Pharmacy Practice | September 2004
References
Gastroenterology 1990;99:629-34.
26. Wesdorp ICE, Dekker W, Festen HPM. Efficacy of
1. DeVault KR, Castell DO. ACG treatment guideline: Updated
guidelines for the diagnosis and treatment of gastroesophageal
reflux disease. Am J Gastroenterol 1999;94:1434-42.
2. Anon. Treatment of gastroesophageal reflux disease
(GERD). Therapeutic letter. Issue 3, Dec 1994, 1-2.
3. Nguyen NQ, Holloway RH. Gastroesophageal reflux
disease. Curr Opin Gastroenterol 2003;19(4):373–8.
4. Fass R. Gastroesophageal reflux disease revisited.
Gastroenterol Clin N Am 2002;31:S1-S10.
5. Shaheen N, Provenzale D. The epidemiology of gastroesophageal reflux disease. Am J Sci 2003;326(5):264-73.
6. Shiau JY, Shukla VK, Dube C. The efficacy of proton pump
inhibitors in adults with functional dyspepsia. Canadian Coordinating Office for Health Technology Report, Jan 2002;22:1-3.
famotidine 20 mg twice a day versus 40 mg twice a day in the
treatment of erosive or ulcerative reflux esophagitis. Dig Dis
Sci 1993;38(12):2287-93.
27. Cloud ML, Offen WW. Nizatidine versus placebo in gastro-esophageal reflux disease: a 6-week multicentre, randomized,
double-blind comparison. Nizatidine Gastroesophageal Reflux
Disease Study Group. Br J Clin Prac Nov 1994 (Suppl);76:11-9.
28. Baldi F, Longanesi A. Nizatidine in gastroesophageal
reflux disease: a review. Gastrointest Res 1991;20:5-6.
29. Richter JE, Campbell DR, Kahrilas PJ, et al.
Lansoprazole compared with ranitidine for the treatment of
nonerosive gastroesophageal reflux disease. Arch Intern Med
2000;160:1803-9.
30. Klinkenberg-Knoll EC, Jansen JM, Festen HP, et al.
7. Williams D. Gastroesophageal reflux disease. In: DiPiro
Double-blind multicentre comparison of omeprazole and ran-
JT, Talbert RL, Yee GC, et al. Pharmacotherapy: a pathophys-
itidine in the treatment of reflux oesophagitis. Lancet
iologic approach. 5th ed. New York: McGraw-Hill Companies
1987;14;349-51.
Inc.; 2002:585-601.
8. Nebel OT, Fornes MF, Castel DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am
J Dig Dis 1976;21:953-6.
9. Akdamar K, Ertan A, Agrawal NM, et al. Upper gastrointestinal endoscopy in normal volunteers. Gastrointest
Endos 1986;32:78-80.
31. Zeitoun P. Comparison of omeprazole with ranitidine
in the treatment of reflux esophagitis. Scan J Gastroenterol
Suppl 1989;166:83-7.
32. Chiba N, De Gara CJ, Wilkinson JM, et al. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux
disease: A metaanalysis. Gastroenterol 1997;112:1798-810.
33. Moore RA, Wiffen P, McQuary HJ, et al. Reflux
10. Locke GR. Natural history of nonerosive reflux dis-
oesophagitis: quantitative systematic review of the evidence
ease: Is all gastroesophageal reflux disease the same? What is
of effectiveness of proton pump inhibitors and histamine anta-
the evidence? Gastroenterol Clin N Am 2002;31:S59-S66.
gonists. University of Wales http://www.jr2.ox.ac.uk/bandolier/
7
ce
Gastroesophageal reflux disease: a review
continuing education lesson
bandopubs/gordf/gord.html (accessed April 10, 2004).
34. van Rensburg CJ, Honiball PJ, Grundling HD, et al.
Efficacy and tolerability of pantoprazole 40 mg versus 80 mg
in patients with reflux oesophagitis. Aliment Phamacol Ther
1996;10:397-401.
35. Vakil N, Fennerty MB. Systematic review: Direct comparative trials of the efficacy of proton pump inhibitors in the
management of gastro-oesophageal reflux disease and peptic
ulcer disease. Aliment Pharmacol Ther 2003;18(6):559-68.
36. Kahrilas PJ, Falk GW, Johnson DA, et al. Esomeprazole
improves healing and symptom resolution as compared with
omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther 2001;14:1249-58.
37. Weaver K. Proton pump inhibitors: subcommittee
report. Oregon health resources commission. July 2003.
38. Lieberman DA, Keefe EB. Treatment of severe reflux
esophagitis with cimetidine and metoclopramide. Ann Intern
Med 1986;104:21-6.
39. Toussaint J, Gossuin A, Deruyttere M, et al. Healing
and prevention of relapse of reflux oesophagitis by cisapride.
Gut 1991;32:1280-5.
Case A
BG is a 59-year-old dentist who asks you for
advice about his heartburn, cough related to acid
indigestion, and laryngitis. He has tried a magnesium/aluminum combination intermittently, up to
one tablespoonful three times a day for weeks
but still has heartburn, cough and regurgitation,
even at night. His profile reveals that he is a
smoker, and that he takes a beta-blocker for
hypertension plus glyburide 5 mg once a day.
Case B
ZM, a 92-year-old female with a history of
seizures, is seen by a specialist because of
intermittent dysphagia, sore stomach (heartburn) and substernal pain. She had coffee
ground emesis seven days ago. Today, she
also has a rash all over her body, likely due
to high-dose naproxen. The specialist suspects
GERD as well as a drug reaction.
Questions
1 Regular use of an antacid with a magnesium/aluminum combination in a patient with
renal failure will likely cause:
a) diarrhea
b) sodium excretion
c) high blood sugar
d) magnesium and aluminum retention
e) none of the above
2 Which of the following is true about famotidine?
a) It can be taken concomitantly with an
antacid.
b) It should be avoided with a beta-blocker.
c) It works within seconds.
3 Antireflux surgery may be recommended in
a patient who has:
a) failed maximum acid suppressive and prokinetic therapy
b) has LES dysfunction
c) either of the above
4 The OTC H2RAs may be recommended as
initial therapy for patients:
a) suffering from heartburn symptoms for a
short period of time
b) with meal-related heartburn
c) both of the above
d) none of the above
5 Patients with non-erosive esophagitis:
a) never develop severe symptoms
b) have positive findings in the endoscopic
exam
c) should never use pharmacologic interventions
d) none of the above
6 A proton pump inhibitor may be preferred
over an H2RA when a patient has:
a) endoscopically documented severe erosive
disease
b) any symptoms
c) neither of the above
7 True or false: Metoclopramide should not be
used in combination with ranitidine in patients
with GERD.
a) True
b) False
8 Helicobacter pylori testing and eradication
is not useful in a patient diagnosed with GERD
because:
a) H. pylori can never be isolated in these
patients
b) H. pylori eradication in GERD is not associated with symptom relief
c) the regimen used for eradication is too
complex for these patients
8
9 How would BG’s GERD symptoms be classified?
a) atypical
b) typical
c) both of the above
10 Which of the following is the most important
question to ask BG?
a) Do you wear tight-fitting clothes and eat
large meals?
b) Do your parents have severe GERD?
c) Have you lost weight, experienced dysphagia or choking, or had any gastrointestinal
bleeding?
11 BG asks you if nicotine causes reflux. You
answer that:
a) smoking lowers LES pressure and contributes to reflux
b) smoking is associated with poor eating
habits that cause heartburn
c) smoking has not been shown to cause or
worsen symptoms of GERD
12 What is the most reasonable advice you
would give to BG about antacids?
a) Triple the dose and take it hourly or more
frequently.
b) Stop taking antacids.
c) Stop the current antacid and try alginic
acid/antacid combination tablets, 2 tabs PC
and HS.
13 Until BG sees a doctor, which of the following is the best advice?
a) Start OTC famotidine 10 mg twice a day.
b) Start lifestyle modifications.
c) Go to a walk-in clinic if “alarm symptoms”
develop.
d) all of the above
14 Endoscopy may be indicated for BG
because:
a) he is on antacids intermittently
b) he has atypical symptoms which may be
due to a more severe form of GERD
c) he is male with hypertension
d) all of the above
15 True or false: Rather than having smaller
and more frequent meals, ZM should have
three standard large meals a day to get symptom relief from GERD.
a) True
b) False
16 The best treatment for ZM is to:
a) stop naproxen and use another NSAID
b) stop naproxen, start a high-dose H2RA and
rule out any cardiac causes or an actively
bleeding ulcer
c) start antacids for control of acid reflux for
two to four weeks, then reassess
d) none of the above
17 True or false: If an electrocardiogram cannot be done immediately, a PPI trial may be recommended for ZM to see if she can get symptom relief. If relieved with a PPI, then cardiacrelated causes of her substernal chest pain may
be ruled out.
a) True
b) False
18 ZM, who has GERD symptoms plus difficulty
swallowing, will benefit from a barium swallow
test because it will reveal if she has:
a) thickening of esophageal folds, strictures or
hiatus hernia
b) Barrett’s esophagus
c) both of the above
19 Long-term use of the prokinetic agent metoclopramide for ZM is not the best choice
because of:
a) the need for frequent administration
b) her age and history of seizure disorder
c) metoclopramide’s side effect profile
d) all of the above
20 True or false: Cimetidine will have the highest risk of side effects for ZM of all the available drugs in the same class of agents.
a) True
b) False
Pharmacy Practice | September 2004
TO ANSWER THIS CE LESSON ONLINE
If currently logged into our ONLINE CE PROGRAM, please return to the "Lessons Available Online"
Page and click on "Link to questions" for this CE Lesson.
If not logged in but already registered to our ONLINE CE PROGRAM, please click here:
http://ce.pharmacygateway.com/Pharmacy/login/index.asp
If you have not registered for our ONLINE CE PROGRAM and wish to answer online, please click
here:
http://ce.pharmacygateway.com/Pharmacy/login/adduser.asp
If you have any questions. Please contact:
Pharmacy Practice, Pharmacy Post, Novopharm CE Compliance Centre, More CCCEP-approved CE’s, or Tech
Talk (English and French CE's)
Mayra Ramos
Fax: (416) 764-3937 or
email: [email protected]
Quebec Pharmacie and L'actualite Pharmaceutique
Stephane Paradis
Fax: (514) 843-2183
email: [email protected]